Tetrazole intermediates to antihypertensive compounds

ABSTRACT

Tetrazole intermediates useful to prepare antihypertensive compounds described in coassigned application U.S. Ser. No. 884,920, filed July 11, 1986, are described, these tetrazoles have the formula: &lt;CHEM&gt; wherein X&lt;1&gt; and X&lt;2&gt; are as described in the specification. n

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to substituted tetrazoles useful as intermediatesin the preparation of antihypertensive compounds described in copendingU.S. patent application, Ser. No. 884,920 Filed July 11, 1986.

S. Kozima et al., J. Organometallic Chem., 33, 337, (1971) and ibid, 92,303 (1975) describes substituted tetrazoles of the formula: ##STR2##wherein R¹ is lower alkyl, benzyl, lower alkenyl or phenyl optionallysubstituted by nitro, lower alkyl, lower alkoxy or halogen; and R² isSnR₃.

R. Lofquist et al., J. Amer. Chem. Soc., 80, 3909 (1958) describessubstituted tetrazoles of the Formula: ##STR3## wherein R is loweralkyl, benzyl, cycloalkyl of 4 carbon atoms, n-heptyl perfluoro, --SR¹where R¹ is lower alkyl, benzyl; --(CH₂)_(n) R² where R² is OH, CO₂ R¹,OR¹, SO₃ Na and n is 1 or 2; or phenyl optionally substituted withamino, lower alkoxy, lower alkyl, nitro or cyano.

W. Beck, et al., Chem. Ber., 116, 2691 (1983) describes the preparationof 2-trityl-5-phenyl tetrazole.

SUMMARY OF THE INVENTION

According to the present invention, there are provided novel compoundsof Formula (I) which are tetrazole intermediates useful for thepreparation of antihypertensive compounds. These tetrazoles have theFormula: ##STR4## wherein X¹ is H, Sn(R)₃, --C(Phenyl)₃, p-nitrobenzyl,or β-propionitrile;

X² is H, Cl, Br, I, O-tosyl, OH, O-mesyl, or ##STR5## R is alkyl of 1-6carbon atoms, phenyl or cyclohexyl; R¹ is alkyl of 3-10 carbon atoms,alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms, andbenzyl substituted with up to two groups selected from alkoxy of 1 to 4carbon atoms, halogen, alkyl of 1 to 4 carbon atoms, nitro and amino;

R² is phenylalkenyl wherein the aliphatic portion is 2 to 4 carbonatoms, --(CH₂)_(m) --imidazoyl-1-yl, --(CH₂)_(m) --1,2,3-triazolyloptionally substituted with one or two groups selected from CO₂ CH₃ andalkyl of 1 to 4 carbon atoms, (CH₂)_(m) -tetrazolyl, ##STR6## R³ is H,F, Cl, Br, I, NO₂, CF₃, or CN; R⁴ is H, alkyl of 1 to 6 carbon atoms,cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl;

R⁵ is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3to 6 carbon atoms, phenyl or benzyl;

R⁶ is H, alkyl of 1-5 carbon atoms, OR⁹ or NR¹⁰ R¹¹ ;

R⁷ is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbonatoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms, phenacyl;

R⁸ is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 carbonatoms, 1-adamantyl, 1-napthyl, 1-(1-napthyl)ethyl, or (CH₂)_(p) C₆ H₅ ;

R⁹ is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbonatoms, or phenyl;

R¹⁰ and R¹¹ independently are H, alkyl of 1 to 4 carbon atoms, phenyl,benzyl or taken together to form a ring of the Formula ##STR7## Q isNR¹², O, or CH₂ ; R¹² is H, alkyl of 1 to 4 carbon atoms, or phenyl;

m is 1 to 5;

n is 1 to 10;

s is 0 to 5;

p is 0 to 3;

t is 0 or 1.

with the proviso that when X¹ =H then X² cannot be ##STR8## Preferredcompounds are those of Formula (I) where: X¹ is H, Sn(R)₃ or--C(phenyl)₃ where R is alkyl of 1 to 6 carbon atoms or phenyl; or

X² is H, Br, Cl, or the substituted imidazole; or

R¹ is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms;

R² is ##STR9## R³ is H, Cl, Br, or I; R⁴ is H, or alkyl of 1 to 4 carbonatoms;

R⁵ is H, or alkyl of 1 to 4 carbon atoms;

R⁶ is H, alkyl of 1 to 5 carbon atoms; OR⁹ ; or N O;

R⁷ is H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to 4 carbon atoms;

R⁸ is CF₃, alkyl of 1 to 6 carbon atoms or phenyl;

m is 1 to 5.

Specifically preferred compounds are those of Formula (I) where:

(1) X¹ is Sn(CH₃)₃, Sn(Ph)₃, Sn(n-Bu)₃, C(Phenyl)₃, or H; and X² is H orBr.

(2) X¹ is Sn(CH₃)₃ or C(Phenyl)₃ ; and X² is ##STR10##

SYNTHESIS

The novel compounds of Formula (I) may be prepared using the reactionsand techniques described in this section. The reactions are performed ina solvent appropriate to the reagents and materials employed andsuitable for the transformation being effected. It is understood bythose skilled in the art of organic synthesis that the functionalitypresent on the imidazole and other portions of the molecule must beconsistent with the chemical transformations proposed. This willfrequently necessitate judgment as to the order of synthetic steps,protecting groups required, deprotection conditions, and activation of abenzylic position to enable attachment to nitrogen on the imidazolenucleus. Throughout the following section, not all compounds of Formula(I) falling into a given class may necessarily be prepared by allmethods described for that class. Substituents on the starting materialsmay be incompatible with some of the reaction conditions required insome of the methods described. Such restrictions to the substituentswhich are compatible with the reaction conditions will be readilyapparent to one skilled in the art and alternative methods must then beused.

Compounds of the Formula (I), where X¹ is Sn(R)₃ and R is alkyl of 1 to6 carbon atoms or phenyl and X² is H or imidazoyl where R¹ is n-butyl,R³ is Cl, and R² is hydroxymethyl may be prepared by the 1,3-dipolarcycloaddition of trialkyltin or triphenyltin azides to the appropriatelysubstituted nitrile (II) (Scheme I). An example of this technique isdescribed by S. Kozima, et al., J. Organometallic Chemistry, 33, 337(1971). The nitrile (II) is described in the coassigned application U.S.Ser. No. 884,920, filed July 11, 1986. Other required nitriles andtrialkyl or triaryl tin azides are either available commercially, or maybe prepared using techniques and methods reported in the chemicalliterature, J. Luijten et al., Rec. Trav. Chem., 81, 202 (1962).##STR11##

Compounds of the Formula (I), where X¹ and X² are H may be prepared byremoval of a suitable protecting group on the tetrazole nucleus.Suitable protecting groups for the tetrazole moiety includep-nitrobenzyl, β-propionitrile, triphenylmethyl, and trialkyltin whichare prepared via the following methods. The nitrobenzyl protecting groupis attached as shown in Scheme II. The acid (IV) is converted to theintermediate acid chloride with oxalyl chloride under standardconditions. The acid chloride is converted to the amide (V) bycondensation with 4-nitrobenzylamine hydrochloride in pyridine in thepresence of a catalytic amount of 4-dimethylaminopyridine (DMAP). Theamide (V) is converted to the intermediate iminoylchloride via reactionwith phosphorus pentachloride in carbon tetrachloride. One example ofthis method is described by H. Ulrich, The Chemistry of Imidoyl Halides,Plenum Press, N.Y., N.Y. (1968). The intermediate iminoyl chloride isconverted to the tetrazole (VI) with lithium azide in dimethylformamide(DMF). An example of this method is described by Elderfield,Heterocyclic Compounds, John Wiley and Sons, (1967). The protectedtetrazole (VI) is then hydrogenated at 50 psi in the presence of acatalytic amount of W6 Raney nickel in ethanol to yield (I). Therequired acid (IV) is available commercially or may be prepared usingtechniques and methods reported in the chemical literature. ##STR12##

The triphenylmethyl group is attached as shown in Scheme III. Thetetrazole (I) reacts with triphenylmethylchloride in methylene chloridecontaining triethylamine as the base under standard conditions to yieldthe protected tetrazole (VII). ##STR13##

The propionitrile protecting group is attached as shown on Scheme IV.The biphenylcarboxylic acid (IV) may be converted to the acid chlorideby a variety of reagents familiar to one skilled in the art. Theintermediate acid chloride reacts with β-aminopropionitrile in thepresence of an acid scavenger such as aqueous sodium hydroxide to yieldamide (VIII). Amide (VIII) reacts with phosphorus pentachloride orphosgene to form the intermediate iminoyl chloride (IX) which whenreacted with hydrazine yields amidrazone (X). The amidrazone (X) reactsreadily with dinitrogen tetroxide (N₂ O₄), which can be convenientlyhandles as a solution in carbon tetrachloride, to yield tetrazole (XI).Hydrazines and hydrazides have been shown to undergo facile conversionto their corresponding azides with N₂ O₄ as described by Y. H. Kim, et.al., Tetrahedron Letters, 27, 4749(1986). The protected tetrazole (XI)is deprotected with aqueous base such as 1N NaOH with or without anadditional organic solvent such as tetrahydrofuran to yield tetrazole(I). The amidrazone (X) may also be converted to the tetrazole (XI)using nitrous acid or its equivalents as described by D. G. Neilson, et.al., Chem. Rev., 70, 151(1970). ##STR14## Preferred protecting groupsare those where X¹ is Sn(R)₃ and C(Phenyl)₃ and R is as describedpreviously (Scheme V). The above groups may be optionally removed viaacidic or basic hydrolysis, catalytic hydrogenation, and irradiationdescribed by Greene, Protective Groups in Organic Synthesis,Wiley-Interscience, (1980). ##STR15##

Compounds of the Formula (I) where X¹ is C(phenyl)₃ and X² is Br may beprepared via radical bromination of (VII) with N-bromosuccinimide (NBS)and dibenzoylperoxide (Bz₂ O₂) to yield (XII) as shown in Scheme VI. Anexample of this conversion is described by L. Horner et al., Angew.Chem., 71, 349 (1959). ##STR16##

Compounds of the Formula (I) where X¹ is C(Phenyl)₃ and X² is I may beprepared via displacement of the bromine moiety in (XII) with sodiumiodide in acetone under standard conditions yielding (XIII).Displacement of the above bromide (XII) with hydroxide ion affords thesubstituted benzyl alcohol (XIV). The benzyl alcohol (XIV) may beconverted to the chloride (XV) via reaction with carbon tetrachlorideand triphenylphosphine. The benzyl alcohol (XIV) can be converted to thetosylate or mesylate (XVI) via reaction with p-toluenesulfonyl chlorideor methanesulfonyl chloride, respectively, in pyridine under standardconditions (Scheme VII). ##STR17##

Compounds of the Formula (I) where X¹ is C(Phenyl)₃ and X² is imidazoylwhere R¹ is n-butyl, R³ is Cl, and R² is hydroxymethyl may be preparedvia alkylation of imidazole (XVII) with the appropriately substitutedbenzyl halide using sodium ethoxide as a base followed by reduction ofthe formaldehyde moiety on imidazole (XVII) to hydroxymethyl with sodiumborohydride affording (XVIII). The preparation of imidazole (XVII) inScheme VIII is described by Furukawa, et. al. in U.S. Pat. No.4,355,040.

The compounds of this invention and their preparation can be understoodfurther by the following examples, but should not constitute alimitation thereof. In these examples, unless otherwise indicated, alltemperatures are in degrees centigrade and parts and percentages are byweight.

EXAMPLE 1 Method A Part AN-trimethylstannyl-5-[2-(4'-methylbiphenylyl)]tetrazole

To a solution of 2-cyano-4'-methylbiphenyl (19.30 g, 0.100 mole) intoluene (110.0 ml) was added trimethyltin azide (24.60 g, 0.120 mole) atroom temperature. The reaction was refluxed for 24 hours, cooled to roomtemperature and the product isolated by filtration affordingN-trimethylstannyl-5-[2-(4'-methylbiphenylyl)]tetrazole (32.60 g, 82%)as an off white solid, m.p. 265° (dec.); ¹ H NMR (DMSO-d₆) δ: 7.50 (s,4H); 7.00 (s, 4H); 2.25 (s, 3H); 0.35 (s, 3H).

Part B 5-[2-(4'-methylbiphenylyl)]tetrazole

To a solution of N-trimethylstannyl-5-[2-(4'-methylbiphenylyl)]tetrazole32.0 g, 0.080 mole) in toluene (230 ml) and tetrahydrofuran (15.0 ml)was bubbled in enough anhydrous hydrogen chloride to give a clearsolution at room temperature. From this solution,5-[2-(4'-methylbiphenylyl)]tetrazole (19.1 g) crystallized.Recrystallization from toluene afforded 18.1 g (95%) of product, m.p.149°-152°. ¹ H NMR (CDCl₃ /DMSO-d₆) δ: 7.50 (m, 4H); 7.07 (m, 4H); 2.35(s, 3H).

EXAMPLE 1 Method B Part A 4'-Methyl-biphenyl-2-carbonyl chloride

A solution of 4'-methyl-biphenyl-2-carboxylic acid (31.84 g, 0.15 mole)in chloroform (200 ml) was added dropwise to a stirred mixture ofchloroform (25 ml) oxalyl chloride (25 ml), and dimethylformamide (1.0ml) at room temperature. After the mixture had stirred for 24 hours atroom temperature, the solution was evaporated in vacuo affording 36.4grams of the crude acid chloride. IR: 1784.0 cm ⁻¹ (COCl).

Part B N-(4-Nitrobenzyl)-4'-methyl-biphenyl-2-carboxamide

A solution of the material from Part A (36.4 g) in dry acetonitrile wasadded dropwise to a cooled (ice-bath), stirred mixture of4-nitrobenzylamine hydrochloride (23.45 g, 0.12 mole), 4-dimethylaminopyridine (0.5 g, 0.0041 mole), and dry pyridine (150.0 ml). After 30minutes, the reaction was allowed to reach room temperature and stirredfor 16 hours at room temperature. The mixture was poured into a stirredmixture of 3N HCl (800.0 ml), ice (400.0 g), and dichloromethane (400ml). The organic layer was washed with 2N NaOH (2×200 ml), brine (100ml), dried (MgSO₄), and evaporated in vacuo to yield crude product (61.9g). Recrystallization from ethyl acetate gave 31.3 (73%) of product,m.p. 153°-154°. ¹ H NMR (CDCl₃) δ: 8.03 (d, 2H, aromatic); 7.65-7.69 (m,1H, aromatic); 7.12-7.48 (m, 7H, aromatic); 7.04 (d, 2H, aromatic);5.77-5.79 (m, 1H, NH); 4.41 (d, 2H, J=6.0 Hz, Ch₂); 2.39 (s, 3H, CH₃).Mass spec m/z=347 (M+1).

Part C N-(4-Nitrobenzyl)-4'-methyl-biphen-2-yl-carboiminoyl chloride

In three portions, a total of 20.78 g (0.060 mole) of the product ofPart B was added to a cooled (ice-bath), stirred solution of phosphoruspentachloride (12.49 g, 0.066 mole) in carbon tetrachloride (200 ml).The mixture was stirred for 30 minutes at 0°, allowed to warm to roomtemperature, and stirred for 16 hours. The mixture was evaporated invacuo yielding the crude product (21.3 g). IR: 1691 cm⁻¹ (C═N). ¹ H NMR(CDCl₃) δ: 4.79 (s, 2H, CH₂).

Part D 1-(4-Nitrobenzyl)-5-(4'-methyl-biphen-2-yl) tetrazole

Lithium azide (3.67 g, 0.75 mole) was added portionwise to a cooledsolution (ice-bath) of the product of Part C (21.3 g) indimethylformamide (200.0 ml). The mixture was allowed to reach roomtemperature over 16 hrs. The reaction mixture was evaporated in vacuo.The residue was partitioned between water and ethyl acetate (100 ml).The organic layer was washed with water (100 ml), dried (MgSO₄) andevaporated in vacuo to yield 19.5 g of a dark residue. Chromatography onsilica (CHCl₃) followed by recrystallization (methanol) afforded 5.37 g,(24.1%), m.p. 95.0°-96.0°. ¹ H NMR (CDCl₃) δ: 7.98-8.02 (m, 2H,aromatic); 7.55-7.70 (m, 2H, aromatic); 7.37-7.49 (m, 2H, aromatic);6.99-7.10 (m, 2H, aromatic); 4.87 (d, J=8.7 Hz, aromatic); 4.88 (s, 2H,CH₂); 2.33 (s, 3H, CH₃). Mass spec m/z =372 (M+1).

Part E 5-[2-(4'-methylbiphenyl)]tetrazole

A mixture of the product of Part D (1.00 g, 2.80 mmole), ethanol (150.0ml), and W6 Raney nickel (5.0 g) was hydrogenated in a Parr® Shaker at50 psi for 2 hrs. at room temperature. The catalyst was removed byfiltration, and the filtrate was evaporated in vacuo. The residue waspartitioned between water and diethyl ether (100 ml) and the organiclayer was washed with 1N HCl (50 ml), brine (50 ml), dried (MgSO₄), andevaporated in vacuo to yield a solid residue which was recrystallizedfrom toluene to yield the product (0.19 g, 28.7%), m.p. 154°-155 °. ¹ HNMR (CDCl₃) δ: 11.5 (br s, 1H, NH); 8.02 (d, 1H, aromatic); 7.38-7.61(m, 3H, aromatic), 7.16 (d, 2H, J=8.0 Hz, aromatic); 7.04 (d, 2H, J=8.0Hz); 2.35 (s, 3H, CH₃). Mass spec m/z=237 (M+1).

EXAMPLE 1 Method C Part A2-(β-cyanoethylaminocarbonyl)-4'-methylbiphenyl

4'-methylbiphenyl-2-carboxylic acid (50.00 g, 0.236 mol,), thionylchloride (87.5 ml, 1.20 mol) and chloroform (500 ml) were mixed andrefluxed for 4 hours. The thionyl chloride and solvent were removed invacuo, and the residue suspended in toluene (300 ml). The mixture wasevaporated in vacuo and the residue suspended once more in toluene andevaporated to insure removal of traces of thionyl chloride. Theresultant acid chloride was dissolved in tetrahydrofuran (100 ml) andslowly added in five equal portions alternatingly with five equalportions of 1.0N NaOH (236.0 ml, 0.236 mol) to a solution ofβ-aminopropionitrile fumarate (30.3 g, 0.236 mol) in 1.0 N NaOH (236.0ml, 0.236 mol) at 0° with stirring. The reaction was allowed to warmslowly to room temperature. After 24 hrs, water (500 ml) was added andthe aqueous mixture extracted with ethyl acetate (3×500 ml). The organiclayers were combined and dried (MgSO₄), and the solvent removed in vacuoto yield a crude solid which, after recrystallization frommethylcyclohexane/butyl chloride, yielded 53.5 g of a white solid.M.P.=102.0°-103.5°. NMR (200 MH_(z), CDCl₃) δ: 7.68 (d, 1H, J=7H_(z));7.56-7.19 (m, 7H); 5.65 (bm, 1H); 3.43 (d of t, 2H); 2.39 (t, 2H,J=7H_(z)). Anal. calcd. for C₁₇ H₁₆ N₂ O; C, 77.25; H, 6.10; N, 10.60.Found: C, 77.42; H, 6.40; N, 10.68.

Part B N³ -(β-cyanoethyl)-4'-methylbiphenyl-2-yl-amidrazone.

2-(β-cyanoethylaminocarbonyl)-4'-methylbiphenyl (33.48 g, 0.127 mol) andphosphorous pentachloride (29.01 g, 0.139 mol) were combined in a roundbottom flask which was then connected to aspirator vacuum via a trapfilled with calcium chloride. The flask was gently heated with a heatgun until the solids melted. The flask was intermittantly heated for15-20 minutes.

The crude iminoyl chloride was taken up in dry dioxane (100 mL) andadded dropwise to a stirred mixture of hydrazine (20.1 mL, 0.634 mol) indry dioxane (200 mL). After 24 hours, the excess hydrazine and solventwere removed in vacuo. Water (300 mL) was added, and the aqueous mixtureextracted with ethyl acetate (3×300 mL). The organic layers werecombined, dried (MgSO₄) and the solvent removed in vacuo to yield anoil. The oil was treated with a 1:1 hexane/ethyl acetate solution (30-50mL), and solids precipated. These were collected and dried to yield16.14 g of light pink solids. M.P.=146.5°-147.5°. Chemical ionizationmass spectrum detected (M+H)⁺ =279 for C₁₇ H₁₈ N₄. Anal. calcl. for C₁₇H₁₈ N₄.(N₂ H₄)₀.1 : C, 72.52; H, 6.44; N, 20.89. Found: C, 72.50; H,6.54; N, 21.13. NMR indicated a mixture of tautomeric forms.

Part C 2-[1-(β-cyanoethyl)-1-H-tetrazol-5-yl]-4'-methylbiphenyl.

A solution of N₂ O₄ (g) in carbon tetrachloride (0.73M, 19.6 mL, 14.3mmol) was added to a stirred slurry of N³(β-cyanoethyl)-4'-methylbiphenyl-2-ylamidrazone (2.00 g, 7.2 mmol) inanhydrous acetonitrile (40 mL) at 0°. The reaction was warmed to roomtemperature and stirred overnight. The solvent was removed in vacuo toyield a crude solid. This solid was taken up in butyl chloride and theinsoluble matter filtered. The filtrate was evaporated, and the residueflash chromatographed on silica in 1:1 hexane/ethylacetate to yield 1.10g of a pale yellow oil, which slowly crystallized. Recrystallizationfrom hexane/butyl chloride yielded 910 mg of pale yellow crystals.M.P.=90.0°-92.0°. NMR (200 MH_(z), CDCl₃) δ: 7.76-7.50 (m, 4H); 7.17 (d,2H, J=10 H_(z)); 7.04 (d, 2H, J=10 H_(z)); 3.80 (t, 2H, J =7 H_(z));2.37 (s, 3H); 2.24 (bt, 2H, J=7H_(z)). Anal. calcd. for C₁₇ H₁₅ N₅ : C,70.57; H, 5.23; N, 24.20. Found: C, 70.49; H, 5.45; N, 24.44.

Part D 5-[2-(4'-methylbiphenylyl)]tetrazole

2-[1-(β-cyanoethyl)-1-H-tetrazol-5-yl]-4'-methylbiphenyl (689 mg, 2.38mmol), 1.0N NaOH (2.62 mL, 2.62 mmol) and THF (15 mL) were mixed andstirred at room temperature. After 15 minutes, water (100 mL) was addedand the pH adjusted to 3.0 with conc. HCl. The aqueous mixture wasextracted with ethyl acetate (3×100 mL) and the organic layers werecombined, dried (MgSO₄) and evaporated in vacuo to yield 550 mg of awhite powder. M.P.=148.5°-150.0°. The spectral data matched those of asample prepared via Method A.

EXAMPLE 5 N-triphenylmethyl-5-[2-(4'-methylbiphenylyl)]tetrazole

To a solution of 5-[2-(4'-methylbiphenlyl)]tetrazole (17.0 g, 0.072mole) in methylene chloride (260 ml) was added triphenylmethyl chloride(21.20 g, 0.076 mole) at room temperature. Triethylamine (12.0 ml, 0.086mole) was added at room temperature, and the solution was refluxed for2.5 hrs. The solution was cooled to room temperature, washed with water(2×50 ml), dried (MgSO₄), and evaporated in vacuo.

The residue was crystallized from toluene (80 ml), yielding,N-triphenylmethyl-5-[2-(4'-methylbiphenylyl)]tetrazole (31.2 g, 90%),m.p. 163°-166°; ¹ H NMR (CDCl₃) δ: 8.10-6.80 (complex, 23H); 2.28 (s,3H).

EXAMPLE 6 N-triphenylmethyl-5-[2-(4'-bromomethyl-biphenylyl)]tetrazole

To a solution of N-triphenylmethyl-5-[2-(4'-methylbiphenylyl)]tetrazole(31.0 g, 0.065 mole) in carbon tetrachloride (390.0 ml) was addedN-bromosuccinimide (11.50 g, 0.065 mole) and dibenzoylperoxide (1.10 g,0.0045 mole) at room temperature. The reaction mixture was refluxed for3 hrs., cooled to 40° and filtered. Evaporation of the filtrate in vacuofollowed by trituration of the residue with isopropyl ether (100.0 ml)yielded N-triphenylmethyl-5-[2-(4'-bromomethyl-biphenylyl)]tetrazole(33.10 g, 92%), m.p. 135°-138°. ¹ H NMR (CDCl₃) δ: 8.20-6.70 (complex,23H); 4.33 (s, 2H).

EXAMPLE 71-{[2'-(N-triphenylmethyl-tetrazol-5-yl)-biphenyl-4-yl]methyl}-2-butyl-4-chloro-5-hydroxymethylimidazole

To a solution of 2-butyl-4-chloro-5-formylimidazole (1.24 g, 0.007 mole)dissolved in dimethylformamide (10.0 ml) was added sodium ethoxide (0.45g, 0.0066 mole) and the reaction mixture was cooled to 5°.N-triphenylmethyl-5-[2-(4'-bromomethylbiphenylyl]tetrazole (3.70 g,0.0066 mole) was added and the reaction mixture was allowed to warm toroom temperature. After 72 hrs. the reaction was diluted with water(25.0 ml) and extracted with ethyl acetate (3×25 ml). The organic phasewas washed with water (2×25 ml) and brine (3×25 ml), dried (MgSO₄), andevaporated in vacuo to an oil. The crude oil was dissolved in methanol(20.0 ml), and sodium borohydride (0.24 g, 0.0063 mole) was added atroom temperature. The reaction was stirred for 1.5 hrs., diluted withwater (40.0 ml), and extracted with ethyl acetate (2×50 ml). The organiclayer was washed with water (1× 25 ml), dried (MgSO₄), and evaporated invacuo. The residue was recrystallized once from toluene/heptane, oncefrom toluene, and finally from methanol to give1-{[2'-(N-triphenylmethyl-tetrazol-5-yl)-biphenyl-4-yl]methyl}-2-butyl-4-chloro-5-hydroxymethylimidazole (0.98 g, 21%), m.p. 95°-98°; ¹ H NMR (CDCl₃) δ: 8.20-6.60(complex, 23H); 5.16 (s, 3H); 4.40 (s, 3H); 2.85 (brs, 1H); 2.54 (t,3H); 1.9-1.1 (m, 4H); 0.88 (t, 3H).

EXAMPLE 81-{[2'-(N-trimethylstannyl-tetrazol-5-yl)-biphenyl-4-yl]methyl}-2-butyl-4-chloro-5-hydroxymethylimidazole

To a solution of1-[(2'-cyano-biphenyl-4-yl)methyl]-2-butyl-4-chloro-5-hydroxymethyl-imidazole(4.40 g, 0.011 mole) in xylenes (40.0 ml) was added trimethyltin azide(2.80 g, 0.014 mole), and the reaction was heated at 115°-120° for 40hrs. The mixture was cooled to 50° and filtered to yield1-{[2'-(N-trimethylstannyl-tetrazol-5-yl)-biphenyl-4-yl]methyl}-2-butyl-4-chloro-5-hydroxymethylimidazole (6.55 g, 99%), m.p. 154°-160°; ¹ H NMR (CDCl₃ /DMSO-d₆) δ:7.80-7.30 (m, 4H), 7.03 (q, 4H), 5.23 (s, 3H), 4.43 (s, 3H), 2.54 (t,3H); 2.00 (s, 1H), 1.80-1.10 (m, 4H); 0.85 (t, 3H); 0.40 (s, 9H).

The compounds of Examples 1, 5, 6, 7, and 8 above as well as othercompounds which were prepared or could be prepared using the proceduresof the aforementioned examples are shown in Table I.

                                      TABLE I                                     __________________________________________________________________________     ##STR19##                                                                    Ex.                                                                              X.sup.1 X.sup.2                                                                           Method                                                                             R.sup.1  R.sup.2   R.sup.3                                                                         M.P. ° C.                     __________________________________________________________________________     1 H       H   A, B, C                                                                            --       --        --                                                                              149-155                               1D                                                                              PNO.sub.2 benzyl                                                                      H   B    --       --        --                                                                              95-96                                 2 Sn(Ph).sub.3                                                                          H   A    --       --        --                                                                              204-209                               3 Sn( -n-Pr).sub.3                                                                      H   A    --       --        --                                                                              --                                    4 Sn(c-C.sub.6 H.sub.11).sub.3                                                          H   A    --       --        --                                                                              --                                    5 C(Phenyl).sub.3                                                                       H   --   --       --        --                                                                              163-166                               6 C(Phenyl).sub.3                                                                       Br  --   --       --        --                                                                              135-138                               7 C(Phenyl).sub.3                                                                       Im  --    -n-Bu   CH.sub.2 OH                                                                             Cl                                                                              95-98                                 8 Sn(CH.sub.3).sub.3                                                                    Im  A     -n-Bu   CH.sub.2 OH                                                                             Cl                                                                              154-160                               9 Sn(Ph).sub.3                                                                          Im  A     -n-Bu   CH.sub.2 OH                                                                             Cl                                     10 Sn( -n-Bu).sub.3                                                                      Im  A     -n-Bu   CH.sub.2 OH                                                                             Cl                                     11 H       OH  --   --       --        --                                     12 C(Phenyl).sub.3                                                                       Cl  --   --       --        --                                     13 Sn(CH.sub.3).sub.3                                                                    Im  A     -n-Pr   CH.sub.2 OH                                                                             Cl                                     14 Sn(Ph).sub.3                                                                          Im  A     -n-Pr   CH.sub.2 OH                                                                             Cl                                     15 Sn( -n-Bu).sub.3                                                                      Im  A     -n-Pr   CH.sub.2 OH                                                                             Cl                                     16 C(Phenyl).sub.3                                                                       Im  --    -n-Pr   CH.sub.2 OH                                                                             Cl                                     17 p-NO.sub.2 C.sub.6 H.sub.4 CH.sub.2                                                   Im  B     -n-Bu   CH.sub.2 OH                                                                             Cl                                     18 Sn(CH.sub.3).sub.3                                                                    Im  A     -n-Bu   CHO       Cl                                     19 C(Phenyl).sub.3                                                                       Im  --    -n-Bu   CHO       H                                      20 Sn(CH.sub. 3).sub.3                                                                   Im  A     -n-Bu   CH.sub.2 NHCO.sub.2 CH.sub.3                                                            Cl                                     21 Sn(CH.sub.3).sub.3                                                                    Im  A     -n-Bu   CH.sub.2 NHSO.sub.2 CH.sub.3                                                            Cl                                     22 C(Phenyl).sub.3                                                                       Im  --    -n-Bu                                                                                  ##STR20##                                                                              Cl                                     23 Sn(CH.sub.3).sub.3                                                                    Im  A     -n-Bu   CH.sub.2 NHSO.sub.2 CF.sub.3                                                            Cl                                     24 C(Phenyl).sub.3                                                                       Im  A     -n-Bu   CH.sub.2 NHSO.sub.2 CF.sub.3                                                            Cl                                     25 Sn(CH.sub.3).sub.3                                                                    Im  A     -n-Bu   CH.sub.2 OH                                                                             H                                      26 C(Ph).sub.3                                                                           Im  --   -n-Bu    CH.sub.2 OH                                                                             H                                      27 Sn(CH.sub.3).sub.3                                                                    Im  A     -n-Bu   CHO       H                                      28 C(Ph).sub.3                                                                           Im  --    -n-Bu   CHO       H                                      29 Sn(CH.sub.3).sub.3                                                                    Im  A    CHCHCH.sub.3                                                                           CH.sub.2 OH                                                                             Cl                                     30 C(Ph).sub.3                                                                           Im  --   CHCHCH.sub.3                                                                           CH.sub.2 OH                                                                             Cl                                     31 Sn(CH.sub.3).sub.3                                                                    Im  A    C CCH.sub.3                                                                            CH.sub.2 OH                                                                             Cl                                     32 C(Ph).sub.3                                                                           Im  --   CCCH.sub.3                                                                             CH.sub.2 OH                                                                             Cl                                     33 CH.sub.2 CH.sub.2 CN                                                                  Im  C     -n-Bu   CH.sub.2 OH                                                                             Cl                                     34 C(Phenyl).sub.3                                                                       I   --   --       --        --                                     35 C(Phenyl).sub.3                                                                       OTs --   --       --        --                                     36 C(Phenyl).sub.3                                                                       OMes                                                                              --   --       --        --                                     37 Sn(CH.sub.3).sub.3                                                                    OH  A    --       --        --                                     38 Sn(Ph).sub.3                                                                          OH  A    --       --        --                                     39 Sn(c-C.sub.6 H.sub.11).sub.3                                                          OH  A    --       --        --                                     __________________________________________________________________________     ##STR21##                                                                

What is claimed is:
 1. A tetrazole having the formula: ##STR22## whereinX¹ is H, --C(Phenyl)₃, p-nitrobenzyl, or β-propionitrile.X² is H, Cl,Br, I, O-tosyl, OH, O-mesyl, or ##STR23## R¹ is alkyl of 3-10 carbonatoms, alkenyl of 3 to 10 carbon atoms, alkynyl of 3 to 10 carbon atoms,and benzyl substituted with up to two groups selected from alkoxy of 1to 4 carbon atoms, halogen, alkyl of 1 to 4 carbon atoms, nitro andamino; R² is phenylalkenyl wherein the aliphatic portion is 2 to 4carbon atoms, --(CH₂)_(m) --imidazoyl-1-yl, --(CH₂)_(m)--1,2,3-triazolyl optionally substituted with one or two groups selectedfrom CO₂ CH₃ and alkyl of 1 to 4 carbon atoms, (CH₂)_(m) -tetrazolyl,##STR24## R³ is H, F, Cl, Br, I, NO₂, CF₃, or CN; R⁴ is H, alkyl of 1 to6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; R⁵is H, alkyl or perfluoroalkyl of 1 to 8 carbon atoms, cycloalkyl of 3 to6 carbon atoms, phenyl or benzyl; R⁶ is H, alkyl of 1-5 carbon atoms,OR⁹ or NR¹⁰ R¹¹ ; R⁷ is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3to 6 carbon atoms, phenyl, benzyl, acyl of 1 to 4 carbon atoms,phenacyl; R⁸ is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6carbon atoms, 1-adamantyl, 1-napthyl, 1-(1-napthyl)ethyl, or (CH₂)_(p)C₆ H₅ ; R⁹ is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6carbon atoms, or phenyl; R¹⁰ and R¹¹ independently are H, alkyl of 1 to4 carbon atoms, phenyl, benzyl or taken together to form a ring of theFormula ##STR25## Q is NR¹², O, or CH₂ ; R¹² is H, alkyl of 1 to 4carbon atoms, or phenyl; m is 1 to 5; n is 1 to 10; s is 0 to 5; p is 0to 3; t is 1.with the proviso that when X¹ =H then X² cannot be##STR26##
 2. The tetrazole of claim 1 wherein X¹ is H or --C(phenyl)₃.3. The tetrazole of claim 1 wherein X² is H, Br, Cl or ##STR27## whereR¹, R² and R³ are as defined in claim
 1. 4. The tetrazole of claim 3whereinR¹ is alkyl, alkenyl or alkynyl of 3 to 7 carbon atoms; R² is##STR28## R³ is H, Cl, Br, or I; R⁴ is H, or alkyl of 1 to 4 carbonatoms; R⁵ is H, or alkyl of 1 to 4 carbon atoms; R⁶ is H, alkyl of 1 to5 carbon atoms or OR⁹ ; R⁷ is H, alkyl of 1 to 4 carbon atoms, or acylof 1 to 4 carbon atoms; R⁸ is CF₃, alkyl of 1 to 6 carbon atoms orphenyl; m is 1 to
 5. 5. The tetrazole of claim 1 wherein X¹ is H, or--C(Phenyl)₃ and X² is H, Br, Cl or ##STR29## where R¹ is alkyl, alkenylor alkynyl of 3 to 7 carbon atoms; R² is ##STR30## R³ is H, Cl, Br, orI; R⁴ is H, or alkyl of 1 to 4 carbon atoms;R⁵ is H, or alkyl of 1 to 4carbon atoms; R⁶ is H, alkyl of 1 to 5 carbon atoms, or OR⁹ ; R⁷ is H,alkyl of 1 to 4 carbon atoms, or acyl of 1 to 4 carbon atoms; R⁸ is CF₃,alkyl of 1 to 6 carbon atoms or phenyl; m is 1 to 5;with the provisothat when X¹ =H then X² is not ##STR31##
 6. The tetrazole of claim 5wherein X² is H, Br or ##STR32## wherein R¹ is alkyl of 3 to 7 carbonatoms;R² is --(CH₂)_(m) OR⁴ where m is 1 to 5 and R⁴ is H or alkyl of 1to 4 carbon atoms; and R³ is Cl.
 7. The tetrazole of claim 6 wherein X²is H.
 8. The tetrazole of claim 6 wherein X² is Br.
 9. The tetrazole ofclaim 6 wherein X² is ##STR33## wherein R¹, R² and R³ are as defined inclaim
 6. 10. The tetrazole of claim 9 wherein R¹ is n-butyl, R² is --CH₂OH and R³ is Cl.